Process for the preparation of drug pellets

ABSTRACT

The object of the invention is a process for the preparation of drug pellets, which method comprises the stages according to which: a drug containing powder is granulated in a rotor type granulator, by exerting a centrifugal force on the powder in the rotor and bringing it, at the periphery of the rotor or adjacent thereto, in contact with a granulating liquid fed separately into the rotor and converted to a mist therein, to which granulating liquid an anti-adhesion agent in an amount of 0.001-5% of the weight of the granulating liquid has been added; the granulate is extruded; and the extrudate obtained is spheronized to pellets which are dried and optionally coated.

This application is a 371 of PCT/FI93/00409, filed Oct. 8, 1993.

The object of this invention is a process for the preparation of drugpellets, which method comprises the stages wherein a drug containingpowder is granulated in a granulator which operates by the rotorprinciple, i.e. in a rotor type granulator, by exerting a centrifugalforce on the powder and, at the periphery of the rotor or in itsvicinity, bringing the powder in contact with a separately fedgranulating liquid converted to a mist to make a granulate, extrudingthe granulate and spheronizing the extrudate obtained into pellets,which are dried and optionally coated.

Drug containing powders to be formulated into drug forms, such aspellets or tablets, seldom exhibit optimal formulation characteristics,such as flow, binding and solubility characteristics. Thus in order toprovide optimal dosage forms the drug thus usually has to be combinedwith various adjuvants and additives which, on the one hand, impart tothe dosage form suitable and desired characteristics and, on the otherhand, facilitate the preparation of the dosage form.

In order to obtain a product of even quality, a granulate is firstformed from the powder mixture containing adjuvants and additives,either by wet or by dry granulation, wherefrom subsequently pellets areformed and/or tablets are compressed.

Adjuvants generally in use in drug forms, such as pellets and tablets,are i.a. lactose, mannitol, microcrystalline cellulose, starch, sucrose,etc., the main purpose of which is to function as a filler or a diluentfor the drug. Their amount as calculated from the final drug form canvary within wide limits, and can constitute even 99% or more of theweight of the whole formulation.

Binders are added to bind the powders and to prepare coherent drugformulations. Generally used binders are, for example, gelatin, variouscellulose derivatives, polyvinyl-pyrrolidone, but also sucrose andstarch may function as a binder. The binder is added either in dry formto the powder, or as a liquid. Binders are generally used in an amountof appr. 2-10% (w/w).

Glidants are added to the dry powders primarily in order to improve thepour and flow characteristics of the powders so that they may be fed atan even rate to the apparatus, thus allowing for the preparation of aproduct which is as homogenous as possible. The glidants are solid;typical glidants are colloidal silicon dioxide, magnesium stearate,starch and talcum. The amount to be added is naturally dependant on thepowder used and also on the glidant, for example magnesium stearate isadded to the powder in an amount of appr. 0.3-1%, whereas the amount oftalcum to be added can be as high as 5%.

In the formulation, besides the above mentioned substances, also otheradjuvants may be used, such as disintegrating agents and pH regulatingagents. Surface active agents, such as polysorbates and sodiumlaurylsulfate have been proposed to be used for improving thewettability of the powder and the solubility of poorly soluble andhydrophobic drugs. It has been stated, however, that the addition ofsurface active agents to the treatment liquid should be avoided as suchan addition makes the pellets so prepared brittle (PharmaceuticalPelletization Technology, Drugs and the Pharmaceutical Sciences, vol.37, Ed. I. Ghebre-Sellassie (Marcel Decker, 1989).

In the granulation, different kinds of mixing apparatuses havetraditionally been used, e.g. high-shear or planetary mixers, which alloperate on the batch principle, that is, they can be used for themanufacture of only one batch at a time. In order to obtain a goodgranulation result with these apparatuses, usually various adjuvantshave to be added, for example binders or even organic solvents.Irrespective of carefully chosen substances and amounts it is not alwayspossible to make, for example, a product which remains even as to itsmoisture content with a mixer of this type. This is naturally a bigdisadvantage especially in the preparation of drug forms. In addition,with regard to many drugs it would be of advantage if it were possibleto eliminate the use of various additives in the drug formulations andthus raise the drug level itself.

According to the invention a method has now been developed which makesit possible to prepare drug pellets of very even quality with anapparatus, which includes a continuously operable granulator and anextruder and a spheronizer associated therewith.

The said granulator is of rotor type, wherein the powder and liquid,under the influence of the centrifugal force generated by a rapidlyrotating rotor, are separately slung towards the periphery of the rotor,where or in the vicinity whereof the liquid dispersed into particulateform (mist) meets the powder and is mixed therewith to form an evengranular mass. Such a mixer is in itself known and described for examplein the EP-publication 254 791. More specifically, such an apparatus isformed by a rotor structure rotating in a housing and comprising,mounted on the same shaft, an upper disc provided, on its upper surface,with powder compartments restricted from above by the housing wall, intowhich compartments the powder is fed at the centre of the rotor, and alower disc, which is spaced from the upper disc, into which space theliquid is fed. The discs rotate at e.g. 1000-5000 rpm, the peripheralspeed being e.g. appr. 300-5000 m/min depending on the diameter of therotor. The liquid is forced from the narrow slotlike space between theupper and lower rotors from its central feeding point towards theperiphery of the rotor, where it exits as a mist through a narrow slitat the periphery of the upper rotor and where it meets the powdersimilarly forced by the centrifugal force towards the periphery, forminga very even granulate.

After granulation, the granulate obtained is fed to an extruder whichpreferably is of radial type, wherein the mass is extruded intoribbonlike bodies through a cylinder shaped perforated wall by means ofrotor blades rotating within the cylinder about a central axis. Further,in the apparatus there are feeding blades rotating in an oppositedirection with respect to the rotor blades, above these. Such anapparatus has been described e.g. in the EP-patent specification 163619. Also other types of extruders can come into question.

After the extrusion stage, the extrudate obtained is spheronized in aspheronizer, for example in an apparatus of the type wherein theextrudate is rotated at great speed over a rotating friction plate. Anapparatus suitable for the purpose is for example an apparatus of Nicaor Caleva type.

According to a preferred embodiment, the different components of theassembly can be interconnected in order to provide for a continuousproduction line, and according to an especially advantageous embodiment,an assembly sold by the trade name Nica Systems, by Nica System Ab,Sweden, is used.

According to the invention it has been found that granulation,especially continuously performed granulation, as well as extrusion andspheronization, especially using a Nica Systems type of apparatus, canbe substantially improved by adding to the granulating liquid a verysmall amount of a selective anti-adhesion agent, namely 0.001 to 5% byweight, but advantageously only 0.01-0.1% by weight, calculated from theweight of the granulating liquid.

As has been described above, glidants have been generally used in theformulation of drug forms, but such agents have been added directly assolid substances to the powder, primarily for improving its flowproperties. According to the invention, however, the anti-adhesion agentis added to the granulating liquid, and the amount to be used accordingto the invention is also substantially smaller than the amounts used asdescribed above.

The term "selective anti-adhesion agent" means in this context an agentwhich on the one hand improves the cohesiveness of the moist mass, andon the other hand prevents the adhesion of the moist mass to the variousparts of the apparatuses used for the preparation. According to theinvention it has been found that it also prevents the adhesion of themoist intermediate products, such as the moist extrudate or the moistpellets, to each other during the various stages of preparation,including drying.

According to the invention it has thus been observed that by adding asmall amount of anti-adhesion agent to the granulating liquid, frictiondeveloped especially in the granulator but also in the extruder, and theresulting heating and adherence of the granular mass to the surfaces,can be eliminated to a substantial degree. This allows for operating theprocess in a continuous manner, with no process disturbances of anykind. In connection with the development of the invention, it has alsobeen observed that without the said addition of anti-adhesion agent, theapparatus is often clogged or other disturbances occur. Overheating mayalso lead to problems with heat-sensitive drugs.

In the extrusion stage, in addition to the benefits mentioned above, theuse of anti-adhesion agent also prevents the formation of a so calledshark-skin extrudate, the further processing of which according toliterature is not feasible as it leads to a wide size distribution rangein the pellets. The anti-adhesion agent as used according to theinvention provides an extrudate with good theological and good surfaceproperties, which properties remain acceptable also during a continuousprocess.

The addition of selective anti-adhesion agent also facilitates thespheronization, while the friction plates, which provide for thespheronizing effect, remain clean and are not filled with drug mass, asis the case without the said agent. This applies also to a continuouslyoperated process. Also the extrudate is spheronized more easily intopellets.

The use of anti-adhesion agent in accordance with the invention thusdecisively improves the running of the process and makes it possible tooperate the same in a continuous manner by assisting in the apparatusremaining clean, which naturally is a substantial advantage. It alsoimproves the quality and evenness of the end product, i.a. providesrounder pellets. Thus the disadvantages of the earlier systems relatinge.g. to variations in the particle size, may be eliminated, and productlosses deriving therefrom, may be reduced.

By using the process according to the invention, the use of binder mayin many cases be abandoned even completely, and pellets of even qualityand with a high concentration of drug (even up to 95% drug) can beproduced from merely a powdered drug and a filler, such amicrocrystalline cellulose. The amount of filler can vary but usually itis at the most 30%, suitably appr. 5-20% by weight of the finalformulation. There is no need to add further adjuvants and additives,but such may of course be added, e.g. buffers.

The selective anti-adhesion agent according to the invention does notbelong to any specific pharmaceutical group of agents, such as forexample lubricants or glidants, but according to the invention suitableanti-adhesion agents are preferably selected from the group formed bypolyols, surface active agents, such as emulsifying and solubilizingagents and stabilizers, or silicone derivatives. Polyols are, forexample, glycerol, propylene glycol, polyethylene glycol, e.g. PEGs200-600 (Shell Chemicals Ltd); surface active agents, e.g. emulsifyingand solubilizing agents and stabilizers are e.g. lecithin, poloxamer(e.g. Pluronic F-68, BASF Ltd), sodium lauryl sulfate (e.g. Tensopol,Tensla Ltd), polysorbates (e.g. Tween, Atlas Chemical In. Ltd), such aspolysorbate 80, sorbitan esters (e.g. Span, Croda Chemicals Ltd),macrogols, dioctyl sodium sulfosuccinate (e.g. Docusate sodium, Manchemltd), sodium laurylsulfonate; and silicone derivatives are e.g. siliconeemulsions (e.g. Dow Corning 365 Medical Grade Emulsion, Dow ChemicalCo.).

As the granulating liquid to which the anti-adhesion agent is addedsuitably for example water or a lower alcohol, e.g. ethanol, or theirmixtures may be used. The amount of granulating liquid needed forgranulation naturally depends on the powder to be granulated, the amountto be used being such which gives the desired rheologicalcharacteristics, and can be easily determined by a person skilled in theart. A suitable amount is usually in the area of 20-100% by weightcalculated from the dry powder mixture, although smaller and largeramounts may be used. The amount of anti-adhesion agent remaining in thefinal formulation thus also depends on the amount of granulating liquidfed, a suitable final concentration varying between appr. 0.0002-5,suitably however appr. 0.002-0.1% by weight of the final product.

The following examples illustrate the invention without limiting thesame in any way.

EXAMPLE 1

Pellets were prepared from powder mixtures containing always 80% byweight of the following drugs: diltiazem HCl, anhydrous theophylline,ibuprofen and paracetamol, as well as 20% by weight of microcrystallinecellulose (Emcocel 90 M, Edward Mendell Co., USA). As the granulatingliquid, distilled water was used which contained 0-0.1% by weight(calculated from the water) of anti-adhesion agent. The anti-adhesionagent was polysorbate for the drugs in question. In the case oftheophylline, also other agents were tested. The feeding rate for thewater was adjusted so that its amount was 65% by weight of the fedpowder mixture.

The drug and the microcrystalline cellulose powder were first mixed for5 minutes in a high-shear-mixer (Fielder PMA 25, GB). The dry mass wasgranulated in a Nica-mixer/granulator (Nica M6L, Sweden). The moist massthus obtained was thereafter extruded in a Nica-extruder (Nica E140,Sweden) and finally spheronized in a Nica-spheronizor (Nica S320,Sweden). The granules were dried either at room temperature or in avented oven.

In the following table the compositions of the final drug forms aregiven.

    ______________________________________                                        Drug                  Emcocel 90                                                                              Polysorbate                                   ______________________________________                                        Diltiazem.HCl                                                                             79.98%    19.99%    0.03%                                         Ibuprofen   79.97%    19.99%    0.04%                                         Paracetamol 79.95%    19.99%    0.06%                                         Theophylline.anh.                                                                         79.95%    19.99%    0.06%                                         ______________________________________                                    

All the drug mixtures performed faultlessly in the process. From all thedrugs, a pellet product was obtained which was of exceedingly evenquality as to size distribution and composition, which product can becoated and/or used as such either as a capsule filling or compressed totablets. The result was good even though the drugs used varied from verywater soluble (diltiazem) to insoluble (ibuprofen).

As regards anhydrous theophylline, it was not possible .to preparepellets which contained more than 50% drug when using plain water asgranulating liquid. The wet mass had in fact very bad self-lubricatingproperties and thus adhered to the apparatus giving rise to overheatingin the mixing and extrusion stage. In order to eliminate this problem,small amounts of various anti-adhesion agents were added to thetheophylline, i.e. those mentioned in the following table. 0.1% byweight of anti-adhesion agent was used calculated from the distilledwater, except for dioctyl sodium sulfosuccinate (DOSS) where the amountadded was 0.01% by weight.

    ______________________________________                                        Composition                                                                   (%)         I        II     III    IV   V                                     ______________________________________                                        Theophylline                                                                              79.95    79.95  79.95  79.95                                                                              79.95                                 Emcocel 90M 19.99    19.99  19.99  19.99                                                                              19.99                                 Polysorbate 80                                                                             0.06                                                             Glycerol              0.06                                                    PEG 300                             0.06                                      Silicone emulsion            0.06                                             (silicone)                                                                    DOSS                                     0.01                                 ______________________________________                                    

According to the invention it was possible to prepare also fromtheophylline pellets of even quality using different anti-adhesionagents.

We claim:
 1. A process for preparation of drug pellets, comprising thesteps of:granulating a drug-containing powder in a rotor-typegranulator; contacting said drug-containing powder with a granulatingliquid to produce a granulate, said granulating liquid comprising ananti-adhesion agent in an amount from about 0.001% to about 5.0% byweight of the granulating liquid; extruding said granulate; spheronizingsaid extruded granulate into pellets; and, drying said pellets.
 2. Theprocess according to claim 1, further comprising the step of convertingsaid granulating liquid to a mist immediately prior to said contactingstep.
 3. The process according to claim 1, further comprising the stepof coating said pellets subsequent to said drying step.
 4. The processaccording to claim 1, wherein said anti-adhesion agent is present insaid granulating liquid in an amount from about 0.01% to about 0.1% byweight.
 5. The process according to claim 1, wherein said anti-adhesionagent is selected from the group consisting of polyols, surface-activeagents, and silicone derivatives.
 6. The process according to claim 5,wherein said anti-adhesion agent is a polyol selected from the groupconsisting of glycerol and polyethylene glycol.
 7. The process accordingto claim 5, wherein said anti-adhesion agent is a surface-active agentselected from the group consisting of polysorbate and dioctyl sodiumsulfosuccinate.
 8. The process according to claim 1, wherein saidgranulating liquid is selected from the group consisting of water andlower alcohols.
 9. The process according to claim 8, wherein saidgranulating liquid is buffered.
 10. The process according to claim 1,wherein said granulating liquid is present in an amount from about 20%to about 100% by weight of the powder.
 11. The process of claim 1,wherein said drug-containing powder comprises a drug selected from thegroup consisting of diltiazem, ibuprofen, theophylline, and paracetamol.12. The process according to claim 1, wherein said drug-containingpowder comprises a filler in an amount up to about 30% by weight of thepowder.
 13. The process according to claim 12, wherein said filler ispresent in an amount from about 5% to about 20% by weight of the powder.14. The process according to claim 12, wherein said filler ismicrocrystalline cellulose.
 15. The process according to claim 1,wherein said process is continuous.
 16. A process for preparation ofdrug pellets, comprising the steps of:granulating a drug-containingpowder in a rotor-type granulator, by exerting a centrifugal force onthe powder in the rotor; contacting said drug-containing powder with agranulating liquid, at the periphery of the rotor or adjacent thereto,to produce a granulate, said granulating liquid comprising ananti-adhesion agent in an amount from about 0.001% to about 5.0% byweight of the granulating liquid; extruding said granulate; spheronizingsaid extruded granulate into pellets; and, drying said pellets.
 17. Theprocess according to claim 16, further comprising the step of coatingsaid pellets subsequent to said drying step.